Composition for enhancing the administration of pharmacologically active agents

ABSTRACT

According to the invention, the parenteral administration of water-insoluble pharmacologically active agents is enhanced wherein the agents are administered in the lipoid phase of a carrier emulsion comprising a microemulsion of a finely dispersed lipoid in an aqueous phase. The lipoid preferably has a mean particle size below 1 micron. This makes it possible to administer water-insoluble agents in high concentrations, and thus a lower dose, whereby a rapid onset of the pharmacological effect is accompanied by a markedly reduced incidence of injury to body tissues.

This application is a division of application Ser. No. 666,264, filedMar. 12, 1976, now U.S. Pat. No. 4,073,943, which is in turn acontinuation-in-part of application Ser. No. 504,880, filed on Sept. 11,1974, now abandoned, which is a continuation-in-part of application Ser.No. 88,474, filed on Nov. 10, 1970, which in turn is acontinuation-in-part of the application Ser. No. 754,738, filed on Aug.22, 1968. Application Ser. Nos. 88,474 and 754,738 have now beenabandoned.

BACKGROUND OF THE INVENTION

It is now a well established fact that a prerequisite for the action ofa drug is its ability to penetrate the lipid cell membranes. A substancecan act only through its undissociated, lipid soluble part. This sets alimitation for the intravenous administration of compounds with a pK_(a)value far from the physiological pH range. On the other hand, a drug hasto be dissolved in a physiological vehicle, which normally is anisotonic aqueous solution. Thus, many drugs can only be administeredorally as tablets or as suspensions, despite the fact that there is amarked therapeutic need for a parenteral route of administration.

The degree of protein binding differs from drug to drug and from speciesto species. The albumin bound part of a drug may be regarded as afloating depot, but it has no pharmacological effect per se. Repeatedadministrations sooner or later give a saturation of the albumin bindingcapacity and finally enough free drug to give a pharmacological effect.

The physiological mechanism of the fat transport in the blood and lymphis by chylomicrons with a median particle diameter between 0.2 and 0.3μm (range 0.05-0.50 μm) and containing phospholipids and protein in themembrane.

In the administration of pharmacologically active agents, it has up tonow mostly been necessary to use water-soluble agents or to transformthe agents into a water-soluble form, so that a solution can be obtainedhaving the properties required for the administration. The use of theagents in a water-soluble form, however, has often had severaldisadvantages. For instance, the aqueous solutions may often be acidicor basic, which may cause side effects. Also, it may sometimes bedifficult to attain a desired effect, as the solutions cannot betolerated by the patient.

It has long been postulated that a higher degree of lipophilisity willsupport an increased pharmacological action of a pharmacon. In 1937Meyer said that "Narcosis commences when any chemical indifferentsubstance has attained a certain molar concentration in the lipids ofthe cell." Until now, it has been difficult to deny or accept thistheory as there was no way to administer these lipophilic andhydrophobic substances so that the pharmacokinetics of the compoundscould not be investigated.

It is known from Remington's Pharmaceutical Sciences, 13th Edition,1965, Page 288, Column 2, Line 23, that "Most stable emulsions haveparticle sizes in the range of 0.25 to 5.0 microns (μ)." However, thereference is to emulsions in general without any appreciation of theutilization of such emulsions for the parenteral administration ofoil-soluble pharmacologically active agents, and more specifically thereis no appreciation that such emulsions can be utilized as a carrieremulsion to enhance the parenteral administration of oil-solublepharmacologically active agents whereby a lower dose rate can beutilized than heretofore to achieve a given effect.

U.S. Pat. No. 2,972,565 to Zilversmit discloses fat concentrates for usein the preparation of fat-in-water emulsions when diluted with water anddisclosed as suitable for intravenous administration. However, we havemade extensive tests in accordance with the examples of the Zilversmitpatent, and all tests have ended in failure. Even with the use of modernhigh-speed emulsifying equipment, it has not been possible to prepareemulsions from Zilversmit's concentrates which have had the small anduniform particle size which is essential in accordance with the presentinvention. When administering placebo emulsions of this type to mice, upto 50% of the test animals have died. The teachings of the patent toZilversmit cannot be considered to lead one skilled in the art to thepresent method of enhancing the parenteral administrations ofoil-soluble pharmacologically active agents.

DESCRIPTION OF THE INVENTION

The present invention now refers to a composition for enhancing theadministering of water-soluble pharmacologically active agents.According to the invention, a method of administering apharmacologically active, oil soluble agent having a diagnostic ortherapeutic effect is disclosed which comprises the steps of dispersinga pharmacologically acceptable lipoid in a pharmacologically acceptableaqueous solution to form an oil-in-water emulsion for stabilizing thedispersion of the lipoid in the form of particles substantially lessthan 4 microns in diameter, and generally of a mean particle size notover 1 micron, predominantly dissolving the active agent in the lipoid,and parenterally administering the emulsion with the active agentdissolved in the lipoid phase thereof. Through this method, an enhanceddiagnostic or therapeutic effect is achieved with a rapid onsetaccompanied by a reduced incidence of injury to body tissues.

By the present invention, the disadvantages mentioned in the backgroundof the invention can be avoided, as the active agents are administereddissolved or dispersed in a system of at least one finely dispersedhydrophobic component in at least one hydrophilic component, andprimarily then in an emulsion or suspension of a pharmacologically inertfat or oil in an aqueous phase. Also, the agents may be used herewithout affecting the pH or the osmotic pressure of the aqueous phase,as the agent will mainly be present in a dissolved or disposed state inthe hydrophobic phase, and will not have any effect on pH or osmoticpressure. Because of this, the method of administration according to theinvention will cause a lower occurrence of injuries to the body tissues.In most cases, the agent also gives a stronger effect and more rapidonset. Unexpectedly, this permits a smaller amount of the agent, i.e. alower dose, to be used to achieve or maintain an effect that wouldotherwise require a significantly higher dose.

The aforementioned protein binding will also be reduced, as the agent isnot in close contact with the proteins. A longer duration of the effectis also obtained in those cases where the agent normally is attackedrapidly by enzymes in metabolic processes. This is a very importantcharacteristic of the present invention: a rapid onset and a good effectwith a longer duration than for the water-soluble salt of the agent. Itis a well known fact that the previous use of oil in injections hasresulted in a slow release of the active agent from the site ofinjection in order to protect the patient from side effects due tooverdosage. See U.S. Pat. No. 3,240,670 (column 1, line 17).

In the past, it has been the opinion of those skilled in the art thatfor parenteral injections, especially then intravenous injection onlyaqueous systems could be used. See, for instance, "Husa's PharmaceuticalDispensing", Mack Publishing Company, Easton, Pa. (196 However, it hasnow been shown that provided the necessary precaution are taken, it isnot only possible to use the new method of administration by parenteralinjection, but even that superior results are attained. In view of theprior art, this is unexpected.

In the use of fat emulsions for intravenous nutrition, a possibility mayalso be stressed. In accordance with the invention, water-insolubleagents for therpeutic or diagnostic purposes may be administered to thepatient simultaneously with the infusion of the fat emulsion.

It may occur that the active agent is not completely dissolved in thehydrophobic phase. It may have a greater affinity to the hydrophobicphase on account of its hydrophobic properties, but depending upon thedistribution equilibria, both of the phases may contain the activeagent. However, according to the most preferred embodiment, the agent ispresent predominantly in the hydrophobic phase, in a dissolved state.

The method of the invention comprises most of the administration waysknown in the medical art, but is especially intended for parenteraladministration, preferably then intravenously, but also intramuscularlyor subcutaneously. Examples of administration methods, other than thosementioned above, are the following:

Parenterally:

intradermally

intraarterially

intraspinally

intrathecally

intrapleurally

intraperitoneally

intrasynovially

Locally

The local administration mentioned above is not intended to refer toexternal local or topical administration, such as an unguent or cream,but rather to an internal local administration, such as directly in anoperation wound and the like, where the emulsion with the active agentgets into a direct contact with the blood and lymph vessels.

The active agents with a therapeutic and/or diagnostic effect, which areto be used in the method of the invention, can be of very varying types,and the selection of these agents is only restricted by the conditionsthat they must be compatible with the vehicle system of several phasesand that no harmful side effects may arise. In all cases an agent willbe used which is soluble in the hydrophobic phase, such an oil-solubleagent, but the agents may then also be partly soluble in the hydrophobicphase and be present in it with the other part as an emulsion orsuspension on account of their greater affinity to this phase. It isalso possible to administer simultaneously oil-soluble and water-solubleagents, each of these primarily being present in the phase to which theyhave the greatest affinity. However, that condition must always besatisfied that it must always be possible to combine the variouscomponents to a stable system with the desired properties, and noharmful side effects must arise.

At room temperature, the active agents are usually solids or liquidswith a boiling point above 140° C. in order to avoid transport from theblood system through the capillaries in the lungs. They may also belower boiling liquids, the salt form of which is solid. In any case, itis necessary that the agents are oil soluble.

Pharmacologically active agents which may be administered in accordancewith the present invention, may be selected, but are not limited to thefollowing groups:

Centrally and peripherally acting agents:

depressants

anaesthetics

analgetics

stimulants

spasmolytics

muscle relaxants

vasodepressants

X-ray contrast agents

In addition to the active agent or agents and the hydrophilic component,which consists of an aqueous solution, and the hydrophobic component,which consists of a pharmacologically inert lipoid, the compositions ofthe invention may contain other substances. These may for instance bepreservatives, agents for pH adjustment, and agents for adjustment ofthe osmotic pressure. One of the most important additives will consistof one or more agents for achieving a stable dispersion of thehydrophobic phase in the hydrophilic phase. Many emulsifiers andsuspension agents of a natural as well as synthetic origin may be used.

The preparations according to the method of the invention may containfrom 1 up to 10 hydrophilic components, and usually they contain about 5hydrophilic components.

As has been indicated above, the carrier or vehicle for the preparationsaccording to the invention consists of a system of at least onehydrophobic component finely dispersed in at least one hydrophiliccomponent. In most cases, the vehicle will consist of an emulsion orsuspension of a fat or an oil in an aqueous solution, both phases ofcourse being pharmacologically acceptable. For this certain conditionsmust be fulfilled. In a finely dispersed system which is to beintroduced into the blood vessels, all the particles must have adiameter below 4 microns, as they will otherwise get stuck in thecapillary vessels. A particle size of 1 micron or less is a salientaspect, and this also makes the system more stable. Moreover, the systemmust also be of such a type that the particles do not form aggregates.Furthermore, the vehicle system must also be able to withstandautoclaving and preferably also freezing, and it must have such acomposition and such properties that it can be stored for a long timewithout physical and chemical breakdown. It is of course also animportant requirement that the vehicle system itself must not causeundesirable effects.

In the vehicle systems most commonly used, which consist of an emulsionor suspension of a pharmacologically inert oil or fat in an aqueoussolution, the hydrophobic component usually consists of a fat or an oilof vegetable or animal origin, such as soybean oil, cottonseed oil,coconut oil or olive oil. In order to obtain a stable system, it isfurthermore necessary to include stabilizers of a natural or syntheticorigin, such as phosphatides, polypropylene glycol, polyethylene glycol,polyglycerol monooleate, etc. The emulsion or suspensions used usuallyhave a fat content of 0.1-99 percent by weight, depending on the form ofapplication. The amount of stabilizer in the compositions is determinedby the properties of the system and depends on the nature of thedissolved active agent and usually lies between 0.1 and 20 weightpercent.

For the purpose of the invention, suitable fat emulsions have beenprepared, and one example of such emulsions is described in the U.S.Pat. No. 3,169,094. This emulsion consists of soybean oil in water withnative egg phosphatides added as a stabilizer, and it has proved to befree from harmful side effects also when administered in such largequantities as are required in intravenous fat nutrition. Other oils orfats and other stabilizers may also be used for the purpose of theinvention, even if they give side effects when used for intravenousnutrition, as they are administered in much smaller quantities when usedas vehicles for pharmaceutically active agents.

The invention is further illustrated by the following examples, which,however, are not limitative.

EXAMPLE 1

5 g of phenyramidol base is dissolved in 95 g of soybean oil. Anemulsion is prepared of 20 g of such a soybean oil solution, 1 g of eggphosphatides, 2.5 g of glycerol and 0.5 g of Myrj 52 (a registered trademark for a nonionic emulsifier consisting of a polyoxyethylenederivative of fatty acids, from Atlas Co, described on page 709 of theMerck Index, 8th Ed., and on page 389 of the Extra Pharmacopoeia,Martindale, 26th Ed.), and sterile water to 100 ml. In the preparation,the conventional precautions for the preparation of bacteriologicallyacceptable injection solutions must be observed.

In pharmacological testing on mice, this composition shows a bettereffect than an aqueous solution of phenyramidol hydrochloride.Furthermore, the aqueous solution also has a lower pH value.

EXAMPLE 2

3.75 g hexobarbital

10 g soybean oil

25 g ethanol

1 g egg phosphatides

0.5 g Myrj 52 (same product as in Example 1)

Sterile water to 100 ml

An emulsion with the above composition is prepared in the same manner asin Example 1. In the finished emulsion, the majority of the particleshave a size below 1 micron.

EXAMPLE 3

Mecamylamine (3-methylaminoisocamphane hydrochloride) is aganglion-blocking secondary amine, and as a base, it is an oily liquidwhich is soluble in lipids. Its toxicity (LD₅₀) after intravenousadministration has been estimated in male albino mice of the NMRI strainin accordance with the method of the Nordic Pharmacopoeia. The followingpreparations were used:

Mecamylamine hydrochloride, 1% dissolved in saline

Mecamylamine base, dissolved in soybean oil and emulsified in theconventional way. Final concentration 1%.

Mecamylamine base, directly emulsified in 5.5% glucose solution with theaid of Pluronic F-68 (a registered trade mark for a nonionic emulsifierconsisting of a block polymer of ethylene oxide and propylene oxide,from Wyandotte Chemical Corporation, described on page 392 of the ExtraPharmacopoeia, Martindale, 26th Edition) and an ultrasonic apparatus(20.000 Hz). Final concentration 1%.

The injections were given in the dorsal tail vein at a speed of 0.1 mlper 5 seconds. The results are listed in Table 1.

                  TABLE I                                                         ______________________________________                                        Intravenous toxicity of different mecamylamine                                preparations in mice.                                                                          LD.sub.50.sup.1                                                                         Survival time                                      Preparation      mg/kg     sec. ± S.E.                                     ______________________________________                                        Mecamylamine HCl 16.3      55 ± 5.1                                                         (15.5- 17.6)                                                 Mecamylamine in oil.sup.2                                                                      15.4      52 ± 3.1                                        emulsion (Intralipid)                                                                          (14.8-16.1)                                                  Mecamylamine in water                                                                          11.9      56 ± 3.8                                        emulsion         (11.4-12.4)                                                  ______________________________________                                         .sup.1 Fiducial limits at P = 0.05                                            .sup.2 "Intralipid" is a registered trade mark for a fat emulsion for         intravenous nutrition. It is described in U.S. Pat. No. 3,169,094.       

The intravenous toxicity of mecamylamine hydrochloride has earlier beenfound to be, by Stone et al.: 21.0 mg/kg [Stone, C. Torchiana, M. L.,Navarro, A. and Beyer, K. H.: "Ganglionic block properties of2-methylaminoisocamphane hydrochloride (Mecamylamine) a secondaryamine", J. Pharmacol. Exptl. Therap.: 117: 169-183 (1956)] and by Corne& Edge: 12.9 mg/kg [Corne, S. J. and Edge, N. D.: "Pharmacologicalproperties of pempidine (1,2,2,6,6-pentamethylpiperidine, a newganglio-blocking compound", Brit. J. Pharmacol.: 13: 339-349 (1958)],which statistically does not differ from the above results.

All the quantal log-dose-response lines had the same slope and acomparison between the hydrochloride and the two emulsions showed aslight increase in toxicity for the pure base preparation, 138%(125-150%), but no difference for the soybean oil preparation, 106%(99-113%), the fiducial limits given at P=0.05.

As can be seen from the table, there was no difference in survival time(the time from the injections to death) between the preparations.

To summarize, it can be stated that the toxic effects of mecamylaminehave not been altered to any notable degree by the different galenicmodifications used.

EXAMPLE 4

The question to be considered here is the influence of protein bindingon a drug, which is dissolved in the oil phase of an emulsion. Quinidineis bound to plasma albumin to an extent of about 80%, and thetherapeutic use of its water soluble salts by intravenous injection maytherefore be hazardous. The individual rate and speed of albumin bindingseems to be more important than the magnitude of the dose given.

A male mongrel dog with an irregular heart rate, between 60 and 130beats per minute, was anaesthesized with urethane, and blood pressure,ventilation, heart rate and ECG were recorded.

Quinidine base, dissolved in soybean oil and suspended in water with afinal concentration of 0.3% was injected into the femoral vein (1mg/kg). A few seconds after the injection was finished, the heart ratewas regulated, and this effect persisted for about 30 minutes.

When a placebo emulsion was administered, no effect could be registered,but when the quinidine injection was repeated, there was again aregulation, which persisted for about one hour.

These results have been followed up in strophantine induced arrythmiasin dogs, and it is found that quinidine base dissolved in oil andemulsified in water is a better and safer preparation for intravenousinjections than aqueous solutions of the quinidine salts.

EXAMPLE 5

Hexobarbital 1%

Hexobarbital--1%

Phospholipids--0.5%

Span 80.sup.(1) --0.05%

Oleic acid--2.5%

Soybean oil--17.5% Glycerol--2.5%

Tween 80.sup.(2) --0.05%

Sterile water to 100%

The emulsion has an instant action when administered intravenously.

Rats:

At a dose of 60 mg/kg, the animals fall asleep without excitation. Aconstant supply of 35 mg/kg gives continuous sleep and afterinterruption of the infusion, the animals wake up after about 3 minutes.

Cats:

The effects of the emulsion on the blood pressure when givenintravenously in a dose of 5-10 mg/kg was registered on achloralose-anaesthetized cat. The emulsion and a solution of sodiumhexobarbital both gave a depression of about 6 mm Hg with about the sameduration.

Mouse:

The sleeping time after a single dose injection of the emulsion wasshorter than the sleeping time after injection of an aqueous solution ofsodium hexobarbital:

    ______________________________________                                                    Sleeping time                                                     Dose          emulsion sodium salt                                            ______________________________________                                        72 mg/kg      130 sec. 172 sec.                                               86 mg/kg      583 sec. 905 sec.                                               ______________________________________                                    

In accordance with common practice, the sleeping time has been set asthe duration of the loss of the righting reflex.

EXAMPLE 6

Chloralose 0.5%

Chloralose--0.5%

Soybean oil--10%

Monoglycid 18/98--10%

Pluronic F-68--0.5%

Glycerol--2.5%

Sterile water to 100%

In rats, an instant sleeping effect was obtained.

EXAMPLE 7

Tribromoethanol 2%

Tribromoethanol--2%

Soybean oil--10%

Span 80--0.14%

Tween 80--0.36%

Phospholipids--0.5%

Glycerol--2.5%

Sterile water to 100%

In rabbits, 80 mg/kg, administered intravenously slowly (5 minutes)gives a light sleep with an onset time of 30 seconds and a duration of 9minutes. The awakening was without remarks.

The following preparations have also been prepared and administered byparenteral injection with good results:

EXAMPLE 8

Pentazocine

Pentazocine--0.05 g

Soybean oil--10 g

Pluronic F-68--0.5 g

Glycerol--2.5%

Sterile water to 100 ml

EXAMPLE 9

Phenylbutazone

Phenylbutazone--2 g

Soybean oil--10 g

Acetylated monoglycerides--10 g

Glycerol--2.5 g

Pluronic F-68--0.5%

Sterile water to 100 ml

EXAMPLE 10

Cyclandelate

Cyclandelate--0.2 g

Soybean oil--15 g

Phosphatides--0.5 g

Pluronic F-68--0.5 g

Glycerol--2.5 g

Sterile water to 100 ml

Cyclandelate (3,5,5-trimethylcyclohexyl mandelate) which is almostcompletely insoluble in water has been administered intraarterially inthe hind leg of cats anaesthetized with chloralose, and in doses ofabout 1-2 mg/kg body weight, causing a marked vasodilatation within afew seconds, especially in noradrenaline induced vasoconstriction. Thesystemic effect (heart rate, blood pressure, etc.) on the circulation ofthe cats was negligible within the dose range used. It has not beenpossible earlier to demonstrate this marked local vasodilating effect,as it has not been possible earlier to administer cyclandelate byinjection.

EXAMPLE 11

Benzocaine

Benzocaine--2 g

Soybean oil--10 g

Monoglyceride--10 g

Glycerol--2.5 g

Span 65--0.5 g

Sterile water to 100 ml

EXAMPLE 12

Secobarbital

Secobarbital--1.5 g

Soybean oil--15 g

Monoglyceride--5 g

Glycerol--2.5 g

Sterile water to 100 ml

EXAMPLE 13

Quatacaine

Quatacainep--0.5 g

Soybean oil--20 g

Pluronic F-108--1 g

Glycerol--2.5 g

Sterile water to 100 ml

EXAMPLE 14

Lidocaine

Lidocaine--2 g

Soybean oil--15 g

Myvacet 9-40--5 g

Pluronic F-103--1 g

Glycerol--2.5 g

Sterile water to 100 ml

"Myvacet 940" is a registered trade mark for acetylated monoglycerides,sold by Distillation Products Co.

EXAMPLE 15

Thiopental

Thiopental--0.75 g

Soybean oil--20 g

Myvacet 9-40--7.5 g

Pluronic L-81--1 g

Glycerol--2.5 g

Sterile water to 100 ml

EXAMPLE 16

Pentobarbital

Pentobarbital--0.75 g

Soybean oil--20 g

Myvacet 9-40--7.5 g

Pluronic F-88--1 g

Glycerol--2.5 g

Sterile water to 100 ml

EXAMPLE 17

In this example, the acute toxicity (LD₅₀) aand the anticonvulsantacitivity of various diazepam formulations has been investigated inmice. In accordance with the invention, diazepam emulsion was preparedwith the following composition:

Diazepam (WHO)--0.5 g

Soybean oil--15.0 g

Acetylated monoglycerides--5.0 g

Egg yolk phosphatidesp--1.2 g

Glycerol--2.5 g

Distilled water to 100.0 ml

This formulation was compared to a commercial diazepam formulation forinjection, which is sold under the registered trade mark Valium fromHoffmann La Roche & Co. This commercial diazepam formulation contains 5mg/ml of diazepam dissolved in an aqueous mixture containing 41.4%propylene glycol, 8.06% ethanol, 1.57% benzyl alcohol, 0.12% benzoicacid and 4.88% sodium benzoate. It is necessary to use this mixture, asdiazepam is not soluble in water alone.

The test results showed that the two formulations had nearly equalanticonvulsant activities, but that the diazepam formulation of theinvention had an LD₅₀ of 283.3 mg/kg, while the LD₅₀ of the commercialdiazepam formulation was 83.4 mg/kg. It is believed that the solventsnecessary in the commercial diazepam formulation contribute in a largedegree to its greater toxicity, and this has been confirmed in a testwith a placebo solution using only the solvents of the commercialdiazepam formulation. This placebo solution had an LD₅₀ of 90.5 mg/kg.

Thus, it has been shown that the administration in accordance with theinvention can be made much safer than in prior methods.

EXAMPLE 18

This example shows how the incidence of injuries in the form ofthromobphlebitis is drastically reduced through the present invention.Thromobphlebites are inflammations in the venous walls, and they cansometimes have quite serious consequences. At intravenous injections,however, they have been such a common occurrence that their appearancehas sometimes not even been noted, but they have been considered as anunavoidable evil. In the use of barbiturates for intravenousanaesthesia, the rate of thrombophlebitis within two weeks afterinjection has been found to be from 10 to 30 percent.

In a comparative test, a commercial 5.5% water solution of Narkotal,trade mark for pronarcon or5-(2-bromoallyl)-5-isopropyl-1-methylbarbituric acid, was administeredintravenously to 53 patients. It was found that within a week, 16 of thepatients, i.e., 30%, developed symptoms of thrombophlebitis. In anothertest, an emulsion prepared in accordance with the invention andcontaining 1.5 percent secobarbital in the oil phase was administeredintravenously in the same way to 62 patients. It was found that none ofthese patients developed any thrombophlebitis symptoms. This clearlyshows that the risk of injuries to the tissues is markedly decreased inthe method of the invention.

EXAMPLE 19

This example shows that it is preferred that the active agent used has aboiling point above 140° C.

An emulsion composition was prepared containing 5 percent ofmethoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether; b.p. 105°C.) in a carrier system of soybean oil emulsified in water with the helpof egg phosphatides. This formulation was administered to mice, and theLD₅₀ value was found to be 150.4 mg/kg.

It was not possible to establish a relation between the sleeping timeand the administered dose. Within a dose range from 118 to 190 mg/kg,the surviving animals slept from 0.6 to 2.0 minutes. There was, however,no correlation between the magnitude of the dose and the sleeping time,and therefore, this cannot be considered as a genuine effect. The reasonfor this is that the methoxyflurane was eliminated through therespiratory tract so quickly that the pharmacological effect was notobtained.

As discussed, a salient aspect of the invention resides in the fact thatthe mean particle size of the lipid particles comprising the inner phaseof the carrier emulsion utilized in carrying forth the present method ispreferably not over 1 mm. To facilitate the practice of the presentinvention the following method is discussed as being suitable for thedetermination of the particle size distribution.

A convenient method to determine the size distribution pattern inparticulate formulations has been published by Groves, Yalabik andTempel Powder Technology 11, 245-255, 1975. Its application in lipidemulsion formulations was described by Groves and Yalabik PowderTechnology, presently in press. The method uses a laser beam andphotodetector as the sensing system for the lipid particles in acentrifugal field and the size distribution is calculated by using thecentrifugal analogue of Stokes' law.

The laser photosedimentometer was used to determine the particle sizedistribution of seven different emulsions of types according to thepresent invention. The factor d_(st)(50) (Stokes' diameter) iscalculated in the particle size determinations. This value indicates themean diameter (at 50%) and the width of the distribution is expressed bythe slope (standard deviation) in TABLE II

                  TABLE II                                                        ______________________________________                                                           Stokes' diameter                                           Emulsion type      d.sub.sr(50) in um                                                                         Slope                                         ______________________________________                                        (1) Fat emulsion 10%   0.15         1.42                                      (2) Fat emulsion 20%   0.23         1.56                                      (3) Fat emulsion 50%   0.50         1.40                                      (4) Emulsion with                                                                 Soy bean + Pluronic F 108                                                                        0.13         2.43                                      (5) Emulsion with Soy bean                                                        oil + Pluronic F 68                                                                              0.63         1.43                                      (6) Diazepam emulsion  0.19         1.41                                      (7) Placebo emulsion                                                              to diazepam        0.25         1.52                                      ______________________________________                                    

While it is believed that the unexpected result obtained by the practiceof the method of the present invention is apparent from the foregoingspecific Examples, particular attention is directed to, for instance,the enhanced administration of the pharmacological agents diazepam andbarbituates, see Examples 17 and respectively.

From a consideration of Example 17 it will be seen that the acutetoxicity of diazepam when administered parenterally in accordance withthe present invention is substantially lower than than of diazepamadministered by a prior parenteral method. In Example 18 it will be seenthat the use of barbituates for intravenous anaesthes administeredparenterally in accordance with the present method result in a markeddecrease of risk of injury to tissues, namely inflammation of the venouswalls thereby greatly enhancing the administration of barbituates forintravenous anaesthesia.

We claim:
 1. A composition for enhancing .[.parenteral.]..Iadd.intravenous .Iaddend.administration comprising a stable,oil-in-water emulsion .Iadd.capable of withstanding autoclaving,.Iaddend.containing a pharmacologically inert lipoid as a hydrophobicphase dispersed in a hydrophilic phase and an effective dose of apharmacologically active, oil-soluble agent predominantly dissolved insaid lipoid at a fraction ratio thereto in the hydrophobic phase, saidlipoid being dispersed in the emulsion as finely divided particleshaving a mean particle size less than 1 micron to achieve rapid onset ofan acceptable therapeutic effect attributable to said effective dose ofthe active agent, said active, .Iadd.oil soluble .Iaddend.agent beingselected from a class of substances consisting of central depressants,analgesics, .[.spasmolytics,.]. muscle relaxants, and vasodepressants..[.2. A composition as defined in claim 1, wherein the oil-solublepharmacological agent is a central depressant from a class of compoundsconsisting of: hexobarbital, secobarbital, thiopental, pentobarbital,and diazepam..]. .[.3. A composition as defined in claim 1, wherein theoil-soluble pharmacological agent is an anaesthetic from a class ofcompounds consisting of: hexylether, tribromoethanol and halothane..]..[.4. A composition as defined in claim 1, wherein the oil-solublepharmacological agent is an analgesic from a class of compoundsconsisting of: pentazocine, phenylbutazone, benzocaine, quatacaine, andlidocaine..]. .[.5. A composition as defined in claim 1, wherein theoil-soluble pharmacological agent is a spasmolytic from a class ofcompounds consisting of: mecamylamine and cyclandelate..]. .[.6. Acomposition as defined in claim 1, wherein the oil-solublepharmacological agent is a vasodepressant from a class of compoundsconsisting of: quinidine and cyclandelate..].
 7. A composition asdefined in claim 1, wherein the .Iadd.pharmacologically active.Iaddend.oil-soluble .[.pharmacological.]. agent is .[.a muscle relaxantfrom the compounds of.]. phenyramidol. .[.8. A composition for enhancingparenteral administration comprising a stable, oil-in-water emulsioncontaining a pharmacologically inert lipoid as a hydrophobic phasedispersed in a hydrophilic phase and an effective dose of apharmacologically active, oil-soluble agent predominantly dissolved insaid lipoid at a fraction ratio thereto in the hydrophobic phase, saidlipoid being dispersed in the emulsion as finely divided particleshaving a mean particle size less than 1 micron to achieve rapid onset ofan acceptable therapeutic effect attributable to said effective dose ofthe active agent, said active agent being selected from a class ofsubstances consisting of: phenyramidol, hexobarbital, mecamylamine,quinidine, chloralose, tribromoethanol, pentazocine, phenylbutazone,cyclandelate, benzocaine, secobarbital, quatacaine, lidocaine,thiopental, pentobarbital, diazepam, and methoxyflurane..]. .Iadd.9. Thecomposition of claim 1 wherein said lipoid contains an oil from thegroup of soybean oil, cottonseed oil, coconut oil, and olive oil..Iaddend. .Iadd.10. The composition of claim 1 which contains astabilizer component containing at least one member selected from thegroup of phosphatide, polypropylene glycol, polyethylene glycol,polyglycerol monooleate, and polyoxyethylene derivative of fattyacids..Iaddend. .Iadd.11. The composition of claim 10 wherein saidstabilizer component includes a phosphatide..Iaddend. .Iadd.12. Thecomposition of claim 10 wherein said member includes polyoxyethylenederivative of fatty acids..Iaddend. .Iadd.13. The composition of claim 1wherein said active agent provides longer duration than for thecorresponding water-soluble salts of the agent..Iaddend. .Iadd.14. Thecomposition of claim 1 wherein said lipoid is soybean oil..Iaddend..Iadd.15. The composition of claim 10 wherein said phosphatide is eggphosphatide..Iaddend. .Iadd.16. The composition of claim 1 which furthercontains glycerol..Iaddend. .Iadd.17. The composition of claim 16wherein the amount of said glycerol is about 2.5% by weight per 100 mlof composition..Iaddend. .Iadd.18. The composition of claim 11 whereinsaid active agent is diazepam and said stabilizer component alsocontains acetylated monoglycerides..Iaddend. .Iadd.19. The compositionof claim 18 wherein the amount of said diazepam is about 0.5 g/100 ml ofcomposition; amount of said phosphatide is about 1.2 g/100 ml ofcomposition; amount of said acetylated monoglyceride is about 5.0 g/100ml; and said lipoid is about 15 g of soybean oil per 100 ml ofcomposition..Iaddend. .Iadd.20. The composition of claim 19 whichfurther contains about 2.5 grams of glycerol..Iaddend. .Iadd.21. Acomposition for enhancing intravenous administration comprising astable, oil-in-water emulsion capable of withstanding autoclavingcontaining a pharmacologically inert lipoid as a hydrophobic phasedispersed in a hydrophilic phase and an effective dose of apharmacologically active, oil-soluble agent predominantly dissolved insaid lipoid at a fraction ratio thereto in the hydrophobic phase, saidlipoid being dispersed in the emulsion as finely divided particleshaving a mean particle size less than 1 micron to achieve rapid onset ofan acceptable therapeutic effect attributable to said effective dose ofthe active agent, wherein said active agent is selected from the groupof chloralose, benzocaine, and secobarbitol; and a stabilizer componentcontaining a monoglyceride..Iaddend. .Iadd.22. A composition forenhancing intravenous administration comprising a stable, oil-in-wateremulsion capable of withstanding autoclaving containing apharmacologically inert lipoid as a hydrophobic phase dispersed in ahydrophilic phase and an effective dose of a pharmacologically active,oil-soluble agent predominantly dissolved in said lipoid at a fractionratio thereto in the hydrophobic phase, said lipoid being dispersed inthe emulsion as finely divided particles having a mean particle sizeless than 1 micron to achieve rapid onset of an acceptable therapeuticeffect attributable to said effective dose of the active agent, whereinsaid active agent is selected from the group of chloralose, pentazocine,cycloandelate, quatacaine, lidocaine, phenylbutazone, thiopental, andpentobarbitol; and a stabilizer component containing a block polymer ofethylene oxide and propylene oxide..Iaddend. .Iadd.23. The compositionof claim 22 which further includes an acylated monoglyceride and whereinsaid active agent is selected from the group of phenylbutazone,lidocaine, thiopental, and pentobarbitol..Iaddend. .Iadd.24. Acomposition for enhancing intravenous administration comprising astable, oil-in-water emulsion capable of withstanding autoclavingcontaining a pharmacologically inert lipoid as a hydrophobic phasedispersed in a hydrophilic phase and an effective dose of hexobarbitolpredominantly dissolved in said lipoid at a fraction ratio thereto inthe hydrophobic phase, said lipoid being dispersed in the emulsion asfinely divided particles having a mean particle size less than 1 micronto achieve rapid onset of an acceptable therapeutic effect attributableto said effective dose of the hexobarbitol..Iaddend. .Iadd.25. Thecomposition of claim 1 which is capable of withstandingfreezing..Iaddend. .Iadd.26. A method for administrating an active agentto a patient which comprises intravenously administering a compositioncomprising a stable, oil-in-water emulsion capable of withstandingautoclaving, containing a pharmacologically inert lipoid as ahydrophobic phase dispersed in a hydrophilic phase and an effective doseof a pharmacologically active, oil-soluble agent predominantly dissolvedin said lipoid at a fraction ratio thereto in the hydrophobic phase,said lipoid being dispersed in the emulsion as finely divided particleshaving a mean particle size less than 1 micron to achieve rapid onset ofan acceptable therapeutic effect attributable to said effective dose ofthe active agent, said active agent being selected from a class ofsubstances consisting of central depressants, analgesics, musclerelaxants, and vasodepressants..Iaddend. .Iadd.27. The method of claim26 wherein said lipoid contains an oil from the group of soybean oil,cottonseed oil, coconut oil, and olive oil..Iaddend. .Iadd.28. Themethod of claim 26 wherein said composition contains a stabilizercomponent containing at least one member selected from the group ofphosphatide, polypropylene glycol, polyethylene glycol, polyglycerolmonooleate, and polyoxyethylene derivative of fatty acids..Iaddend..Iadd.29. The method of claim 28 wherein said stabilizer componentincludes a phosphatide..Iaddend. .Iadd.30. The method of claim 28wherein said member includes polyoxyethylene derivative of fattyacids..Iaddend. .Iadd.31. The method of claim 26 wherein said activeagent provides longer duration than for the corresponding water-solublesalts of the agent..Iaddend. .Iadd.32. The method of claim 26 whereinsaid lipoid is soybean oil..Iaddend. .Iadd.33. The method of claim 28wherein said phosphatide is egg phosphatide..Iaddend. .Iadd.34. Themethod of claim 26 wherein said composition further containsglycerol..Iaddend. .Iadd.35. The method of claim 34 wherein the amountof said glycerol is about 2.5% by weight per 100 ml ofcomposition..Iaddend. .Iadd.36. The method of claim 26 wherein saidactive agent is phenyramidol..Iaddend. .Iadd.37. The method of claim 29wherein said active agent is diazepam and said stabilizer component alsocontains acetylated monoglycerides..Iaddend. .Iadd.38. The method ofclaim 37 wherein the amount of said diazepam is about 0.5 g/100 ml ofcomposition; amount of said phosphatide is about 1.2 g/100 ml ofcomposition; amount of acetylated monoglyceride is about 5.0 g/100 ml;and said lipoid is about 15 g of soybean oil per 100 ml ofcomposition..Iaddend. .Iadd.39. The method of claim 38 wherein saidcomposition further contains about 2.5 grams of glycerol..Iaddend..Iadd.40. The method of claim 26 wherein said composition is capable ofwithstanding freezing..Iaddend. .Iadd.41. A method for administrating anactive agent to a patient which comprises intravenously administering acomposition comprising a stable, oil-in-water emulsion capable ofwithstanding autoclaving containing a pharmacologically inert lipoid asa hydrophobic phase dispersed in a hydrophilic phase and an effectivedose of a pharmacologically active, oil-soluble agent predominantlydissolved in said lipoid at a fraction ratio thereto in the hydrophobicphase, said lipoid being dispersed in the emulsion as finely dividedparticles having a mean particle size less than 1 micron to achieverapid onset of an acceptable therapeutic effect attributable to saideffective dose of the active agent, wherein said active agent isselected from the group of chloralose, benzocaine, and secobarbitol; anda stabilizer component containing a monoglyceride..Iaddend. .Iadd.42. Amethod for administrating an active agent to a patient which comprisesintravenously administering a composition comprising a stable,oil-in-water emulsion capable of withstanding autoclaving containing apharmacologically inert lipoid as a hydrophobic phase dispersed in ahydrophilic phase and an effective dose of a pharmacologically active,oil-soluble agent predominantly dissolved in said lipoid at a fractionratio thereto in the hydrophobic phase, said lipoid being dispersed inthe emulsion as finely divided particles having a mean particle sizeless than 1 micron to achieve rapid onset of an acceptable therapeuticeffect attributable to said effective dose of the active agent, whereinsaid active agent is selected from the group of chloralose, pentazocine,cycloandelate, quatacaine, lidocaine, phenylbutazone, thiopental, andpentobarbitol; and a stabilizer component containing a block polymer ofethylene oxide and propylene oxide..Iaddend. .Iadd.43. The method ofclaim 42 wherein said composition further includes an acylatedmonoglyceride and wherein said active agent is selected from the groupof phenylbutazone, lidocaine, thiopental, and pentobarbitol..Iaddend..Iadd.44. A method for administrating an active agent to a patient whichcomprises intravenously administering a composition comprising a stable,oil-in-water emulsion capable of withstanding autoclaving containing apharmacologically inert lipoid as a hydrophobic phase dispersed in ahydrophilic phase and an effective dose of hexobarbitol predominantlydissolved in said lipoid at a fraction ratio thereto in the hydrophobicphase, said lipoid being dispersed in the emulsion as finely dividedparticles having a mean particle size less than 1 micron to achieverapid onset of an acceptable therapeutic effect attributable to saideffective dose of the hexobarbitol..Iaddend.